Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3-(2″-hydroxy naphthalen-1″-yl)-1,5-diphenyl-2-pyrazolines

Article abstract of DOI:10.1016/j.bmcl.2005.08.040

Five new 1,3,5-triphenyl-2-pyrazolines were synthesised by reacting 1,3-diphenyl-2-propene-1-one with phenyl hydrazine hydrochloride and another five new 3-(2″-hydroxy naphthalen-1″-yl)-1,5-diphenyl-2-pyrazolines were synthesised by reacting 1-(2′-hydroxy

Full text of DOI:10.1016/j.bmcl.2005.08.040

Bioorganic & Medicinal Chemistry Letters 15 (2005) 5030–5034
Synthesis and antidepressant activity of some
1,3,5-triphenyl-2-pyrazolines and 3-(200-hydroxy
naphthalen-100-yl)-1,5-diphenyl-2-pyrazolines
Y. Rajendra Prasad,* A. Lakshmana Rao, L. Prasoona, K. Murali and P. Ravi Kumar
University College of Pharmaceutical Sciences, Andhra University, Visakapatnam 530003, Andhra Pradesh, India
Received 25 April 2005; revised 31 July 2005; accepted 1 August 2005
Available online 15 September 2005
Abstract—Five new 1,3,5-triphenyl-2-pyrazolines were synthesised by reacting 1,3-diphenyl-2-propene-1-one with phenyl hydrazine
hydrochloride and another five new 3-(200-hydroxy naphthalen-100-yl)-1,5-diphenyl-2-pyrazolines were synthesised by reacting 1-(20-
hydroxynaphthyl)-3-phenyl-2-propene-1-one with phenyl hydrazine hydrochloride. The structures of the compounds were proved
by means of their IR, 1H NMR spectroscopic data, and microanalyses. The antidepressant activity of these compounds was evaluated
by the ÔPorsolt behavioural despair testÕ on Swiss-Webster mice.1-Phenyl-3-(200-hydroxyphenyl)-5-(40-dimethylaminophenyl)-2-pyraz-
oline, 5-(40-dimethylaminophenyl)-1,3-diphenyl-2-pyrazoline, 1-phenyl-3-(200-hydroxynaphthalen-100-yl)-5-(30,40,50-trimethoxyphe-
nyl)-2-pyrazoline, 1-phenyl-3-(400-methylphenyl)-5-(40-dimethylaminophenyl)-2-pyrazoline and 1-phenyl-3-(400-bromophenyl)-5-(40-
dimethyl amino phenyl)-2-pyrazoline reduced immobility times 25.63–59.25% at 100 mg/kg dose level. In addition, it was found
that the compounds possessing electron-releasing groups such as dimethyl amino, methoxy and hydroxyl substituents, on both the
aromatic rings at positions 3 and 5 of pyrazolines, considerably enhanced the antidepressant activity when compared to the pyrazolines
having no substituents on the phenyl rings.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Considerable interest has been focused on the pyrazoline
structure, which has been known to possess a broad
spectrum of biological activities such as tranquillizing,
muscle relaxant, psychoanaleptic, anticonvulsant, anti-
hypertensive, and antidepressant activities.1–6 The dis-
covery of this class of drugs provides an outstanding
case history of modern drug development and also
points out the unpredictability of biological activity
from structural modification of a prototype drug mole-
cule. Prodrug-based monoamine oxidase (MAO) inhibi-
tors having hydrazide, hydrazine, and amine moiety
such as isocarboxazide,7 phenelzine,8 and meclobe-
mide9,10 show prominent antidepressant activity in
laboratory animals, and human. Additionally, tranyl-
cypromine-like MAO inhibitors are mechanism-based
inactivators and they are metabolized by MAO with
one electron of the nitrogen pair and to generate an
imine, the other residing on a methylene carbon
(R-C@NH2+). The structures of the synthesised 2-pyraz-
oline derivatives are very similar to those of isocarbox-
azid (Fig. 1). Earlier studies by Parmar et al.3 and
Soni et al.4 demonstrated monoamine oxidase inhibitory
activities of some 1,3,5-triphenyl-2-pyrazolines,1-thioc-
arbamoyl-3,5-diphenyl-2-pyrazolines and bicyclic pyraz-
olines in behavioural despair test.11–14 As part of our
efforts in this area, a series of some new 1-phenyl-3-(200
and/or 400-substituted phenyl)-5-(30-and/or 40-substituted
phenyl)-2-pyrazolines and 1-(phenyl)-5-(20- and/or 30-
and/or 40-substituted phenyl)-3-(200-hydroxy-naphtha-
len-100-yl)-2-pyrazolines have been synthesised and
evaluated for their antidepressant activities using
ÔBehavioural despair testÕ.
In the present work, 1,3-diphenyl-2-propen-1-ones (1a–e
)
and 1-(20-hydroxy naphthyl)-3-phenyl-2-propene-1-ones
were synthesised by condensing appropriate acetophe-
nones with benzaldehyde derivatives in dilute ethanolic
potassium hydroxide solution at room temperature
according to Claisen–Schmidt condensation.15–17 The
1,3,5-triphenyl-2-pyrazolines (2a–e) were synthesised by
Keywords: Antidepressant activity; 1,3,5-Triphenyl pyrazolines;
3-(200-Naphthalen-100-yl)-1,5-diphenyl-2-pyrazolines; Forced-swimming
test.
*
Corresponding author. Tel.: +91 891 2504224; fax: +91 891
2525611; e-mail: dryrp@rediffmail.com
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.040

Y. Rajendra Prasad et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5030–5034
5031
H
R2
H
H
R1
H H
H
H
H H
H
H
R1
R4
H
H
H
H
R3
R4
R2
R3
H
H
OH
N
N
O
N
H
N
H
H
N
N
H
H
H
H
H
H
H
N
H
H
H
H
O
H
H
H
H
H
1,3,5-Triphenyl-2-pyrazolines (2a-e
)
3-(2''-hydroxy napthalen-1''-yl)
Isocarboxazid
-1,5-diphenyl-2-pyrazolines (4a-e
)
Figure 1. Structures of 1,3,5-triphenyl-2-pyrazolines (2a-e), 3-(200-hydroxy naphthalen-100-yl)-1,5-diphenyl-2-pyrazolines (4a-e) and isocorboxazid.
the reaction of 0.01 mol of appropriate 1,3-diphenyl-2-
propen-1-one derivatives (1a–e) in 15 ml ethanol with
0.02 mol phenyl hydrazine hydrochloride according
to the condensation reaction of unsaturated ketones
with hydrazines. 3-(200-Hydroxy naphthalen-100-yl)-1,5-
diphenyl-2-pyrazolines (4a–e) were synthesised by the
reaction of appropriate 1-(20-hydroxy naphthyl)-3-phen-
mice by using the Porsolt behavioural despair test. This
test is effective in predicting the antidepressant activity
of a wide variety of new molecules.18,19 The Porsolt
forced-swimming induced behavioural despair model
is capable of predicting a variety of potential antide-
pressants, yet it is not devoid of biases. However, its
validity is unclear, because it gives false-positive results
in cylinders with 10 cm diameter in the case of central
nervous system (CNS) stimulants, anticholinergics, and
antihistaminics. Moreover, mice in the 10 cm chambers
touch the cylinder wall and bottom with their fore and
hind paws. Therefore, the data may not reflect the true
immobility times. In the modified behavioural despair
test method,20 with an increase in diameter of the cyl-
inder, mice lose their chance to touch the sides and the
bottom of the cylinder and thus are forced to swim and
the duration of immobility in 30 cm diameter cylinders
was significantly lower than in 10 cm cylinders. The
most striking result obtained by increasing the diame-
ter of the cylinder was that the anticholinergics,
antihistiminics, and CNS stimulants did not give
false-positive results when the duration of immobility
was used as the criterion. Parmar et al.3 investigated
the ability of some substituted pyrazolines to inhibit
yl-2-propene-1-ones (3a–e
)
with phenyl hydrazine
hydrochloride in a similar way in yields varying from
78% to 91% (Schemes 1 and 2).
Structure and chemical data of the synthesised com-
pounds are given in Table 1. IR spectra of the com-
pounds showed C@N stretching band at 1590 cmꢀ1
.
In the 1H NMR spectra, HA, HB and Hx protons
of the pyrazoline ring were seen as doublet of dou-
blets at 3.07–3.25, 3.75–3.88, and 5.15–5.30 ppm
(JAB = 17, JAX = 7 and JBX = 10 Hz). The protons
belonging to the aromatic ring and substituent groups
were observed within the expected chemical shift val-
ues (Table 2).
The synthesised compounds were evaluated for antide-
pressant activity in Adult male albino Swiss-Webster
R1
R3
R1
R3
R2
C CH3
O
OHC
R4
+
R2
C CH CH
O
R4
KOH
1a-e
R1
C6H5NHNH2 .HCl
R3
R4
R2
N
N
2a-e
Scheme 1. Synthesis of 1,3,5-triphenyl-2-pyrazolines.

5032
Y. Rajendra Prasad et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5030–5034
R1
R2
R4
R1
R2
R4
C
O
OH
CH3
R3
OHC
R3
+
C
O
OH
CH CH
KOH
(3a-e)
C6H5NHNH2 .HCl
R1
R2
N
OH
R3
R4
N
(4a-e)
Scheme 2. Synthesis of 3-(200-hydroxy naphthalen-100-yl)-1,5-diphenyl-2-pyrazolines.
Table 1. Structure and chemical data of the compounds 2a–e and 4a–e
R1
R3
R4
R2
R1
R2
N
R3
N
N
OH
N
R4
(2a-e)
(4a-e)
Compound
R1
R2
R3
R4
Formula
Melting point (ꢁC)
Yield (%)
2a
2b
2c
2d
2e
4a
4b
4c
4d
4e
–H
–H
–OH
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
–N(CH3)2
–N(CH3)2
–N(CH3)2
–N(CH3)2
–H
C23H23N3(C,H,N)a
C24H25N3(C,H,N)
120
140
178
172
128
238
240
246
252
258
80
78
85
89
79
84
91
83
86
90
–CH3
–H
–Br
–H
–H
C23H23N3O(C,H,N)
C23H22N3Br(C,H,N)
C21H17BrN2O(C,H,N)
C25H20N2O(C,H,N)
C26H22N2O2(C,H,N)
C25H19ClN2O(C,H,N)
C25H19BrN2O(C,H,N)
C28H26N2O4(C,H,N)
–OH
–H
–Br
–H
–H
–H
–H
–H
–OCH3
–Cl
–Br
–H
–H
–H
–OCH3
–OCH3
–OCH3
a Elemental analyses for C, H and N are within 0.4% of the theoretical values.
rat brain MAO and indicated that the presence of elec-
tron donating substituent on the phenyl ring present at
position 5 of the pyrazoline ring produced a relatively
higher degree of MAO inhibition, while electron-with-
drawing substituents produced a lesser degree of en-
zyme inhibition.
w/v, 0.9% NaCl). All the synthesised compounds
(100 mg kgꢀ1) and clomipramine (10 and 20 mg kgꢀ1
)
were injected intraperitoneally to mice at a volume of
0.5 ml per 100 g body weight. One hour later, the mice
were dropped one at a time into a plexiglass cylinder
(25 cm height, 30 cm diameter containing water to a
height of 20 cm at 21–23 ꢁC) and left for 6 min. At the
end of the first 2 min, the animals showing initial vigor-
ous struggling were immobile. Then the immobility
times of each mouse were measured in the next 4 min
period.
The mice (22 2 g) were housed in plexiglass cages with
six animals for each cage in a quiet and temperature and
humidity controlled room (22 3 ꢁC and 60 5%,
respectively) in which a 12 h light dark cycle was main-
tained (08:00–20:00 h light). On the testing day, mice
were assigned to different groups (n = 6 for each group).
The synthesised compounds and the standard drug clo-
mipramine were suspended in aqueous Tween 80 (0.2%
From the results it may be observed that compounds
1-phenyl-3-(200-hydroxyphenyl)-5-(40-dimethylaminophenyl)-2-
pyrazoline, 5-(40-dimethylaminophenyl)-1,3-diphenyl-2-

Y. Rajendra Prasad et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5030–5034
Table 2. Spectral data of compounds 2a–eand 4a–e
R1
5033
HA
R3
HB
R2
HA
R1
HB
R2
R4
N
R4
N
N
R3
HX
N
OH
HX
2a-e
4a-e
Compound
IR (KBr, cmꢀ1
)
1H NMR (CDCl3, ppm)a
2a
1600, 1520 (C@C, C@N); 1065 (C–N)
2.92 (6H, s, –N(CH3)2), 3.11 (1H, dd, HA), 3.80 (1H, dd,
HB), 5.23 (1H, dd, HX), 6.69–7.87 (14H, m, Ar-H),
(JAB = 16.98, JAX = 7.50, JBX = 9.35 Hz)
2b
2c
2d
2e
4a
1595, 1522 (C@C, C@N); 1070 (C–N)
2.37 (3H, s, Ar-CH3), 2.92 (6H, S, –N(CH3)2), 3.11 (1H,
dd, HA), 3.78 (1H, dd, HB), 5.17 (1H, dd, HX), 6.67–7.63
(13H, m, Ar-H), (JAB = 16.50, JAX = 7.80, JBX = 9.90 Hz)
3100 (–OH); 1600, 1520 (C@C, C@N); 1075 (C–N)
1605, 1525 (C@C, C@N); 1080 (C–N); 855 (–C–Br)
3100 (–OH); 1605, 1522 (C@C, C@N); 1081 (C–N); 857 (–C–Br)
3100 (–OH); 1640 (C@N); 1350 (C–N)
2.92 (6H, s, –N(CH3)2), 3.25 (1H, dd, HA), 3.88 (1H, dd,
HB), 5.15 (1H, dd, HX), 10.85 (1H, s, C-2-OH), 6.65–7.28
(13H, m, Ar-H), (JAB = 16.92, JAX = 6.98, JBX = 9.80 Hz)
2.92 (6H, s, –N(CH3)2), 3.10 (1H, dd, HA), 3.75 (1H, dd,
HB), 5.22 (1H, dd, HX), 6.74–7.60 (13H, m, Ar-H),
(JAB = 17.05, JAX = 7.10, JBX = 9.65 Hz)
3.15 (1H, dd, HA), 3.80 (1H, dd, HB), 5.15 (1H, dd, HX),
6.74–7.80 (13H, m, Ar-H), (JAB = 17.25, JAX = 7.30,
JBX = 9.67 Hz)
3.07 (1H,dd, HA), 3.85 (1H, dd, HB), 5.30 (1H, dd, HX),
6.80–7.95 (15H, m, Ar-H), 9.90 (1H, d, J = 9 Hz, C-8-H),
10.30 (1H, s, C-2-OH), (JAB = 16.78, JAX = 6.95,
JBX = 9.35 Hz)
4b
4c
4d
3110 (–OH); 1642 (C@N); 1355 (–C–N); 1160 (–OCH3)
3050 (–OH); 1645 (C@N); 1350 (–C–N); 855 (–C–Cl)
3050 (–OH); 1640 (C@N); 1352 (–C–N); 860 (–C–Br)
3.12 (1H, dd, HA), 3.76 (1H, dd, HB), 3.90 (3H, s, C-4-
OCH3), 5.28 (1H, dd, HX), 9.70 (1H, d, J = 9Hz, C-8-H),
(JAB = 17.10, JAX = 6.90, JBX = 9.48 Hz)
3.08 (1H, dd, HA), 3.78 (1H, dd, HB), 5.15 (1H, dd, HX),
6.90–7.90 (14H, m, Ar-H), 9.70 (1H, d, J = 9 Hz, C-8-H),
(JAB = 17.05, JAX = 6.99, JBX = 9.35 Hz)
3.16 (1H, dd, HA), 3.88 (1H, dd, HB), 5.25 (1H, dd, HX),
6.80–7.90 (14H, m, Ar-H), 9.50 (1H, d, J = 9 Hz, C-8-H),
13.50 (1H, s, C-2-OH), (JAB = 16.88, JAX = 7.89,
JBX = 10.25 Hz)
4e
3120 (–OH); 1640 (C@N); 1350 (–C–N); 1180 (–OCH3)
3.11 (1H, dd, HA), 3.86 (3H, s, –O–CH3), 3.85 (1H, dd,
HB), 3.90 (6H, s, 2·-O–CH3), 5.24 (1H, dd, HX), 9.72 (1H,
d, J = 9 Hz, C-8-H), 6.90–7.95 (12H, m, Ar-H),
(JAB = 17.38, JAX = 7.48, JBX = 9.62 Hz)
a s, singlet; dd, doublet of doublets; m, multiplet.
pyrazoline, 1-phenyl-3-(200-hydroxynaphthalen-100-yl)-5-
(30,40,50-trimethoxyphenyl)-2-pyrazoline,1-phenyl-3-(400-
methylphenyl)-5-(40-dimethylaminophenyl)-2-pyrazoline
and 1-phenyl-3-(400-bromophenyl)-5-(40-dimethyl ami-
nophenyl)-2-pyrazoline reduced immobility times
25.63–59.25% at 100 mg kgꢀ1 dose level. The results re-
vealed that the compounds possessing electron-releasing
groups such as dimethylamino, methoxy, and hydroxyl
substituents, on both the aromatic rings at positions 3
and 5 of pyrazolines, considerably enhanced the antide-
pressant activity when compared to the pyrazolines hav-
ing no substituents on the phenyl rings and this is
consistent with the observation made earlier by Parmar
et al.3 (Table 3).
Statistical significance was set at P < 0.05 level.
Changes in duration of immobilizations expressed
as means SEM were evaluated using DunnetÕs
test (Pharmacological Calculation System, version
4.1).

5034
Y. Rajendra Prasad et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5030–5034
Table 3. Antidepressant activity of the compounds
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Compounda
Duration of immobility(s)
% change from
controlb
2a
2b
22.95 4.21
50.15 5.45
35.85 4.20
41.88 2.86
32.46 4.63
50.33 6.88
50.78 4.58
46.28 4.39
25.40 3.33
49.26 4.70
33.81 3.98
ꢀ59.25
ꢀ10.95
ꢀ36.34
ꢀ25.63
ꢀ42.18
ꢀ10.63
ꢀ9.83
2c
2d
2e
4a
4b
4c
4d
ꢀ17.82
ꢀ54.10
ꢀ12.53
ꢀ39.96
4e
Clomipramine
(10 mg/kg)
Clomipramine
(20 mg/kg)
Control
(Vehicle)
18.68 2.25
56.32 7.14
ꢀ66.93
—
a Compounds were tested at 100 mg kgꢀ1 dose level, ip.
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b 95% confidence limits (DunnetÕs test), n = 6.
Acknowledgments
The authors thank the head, Sophisticated Instrumenta-
tion Facility, Indian Institute of Sciences, Bangalore, for
1H NMR spectra and Sipra Laboratories, Hyderabad,
for IR spectra and financial support. We also wish to
acknowledge the help rendered by Dr. A. Annapurna,
associate professor in pharmacology, in carrying out
the antidepressant activity.
14. Palaska, E.; Erol, D.; Demirdamar, R. Eur. J. Med. Chem.
1996, 31, 43.
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